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• W2032020008 abstract "Fatty acids are an important class of signaling molecules regulating key aspects of whole body metabolism and physiology. In this issue, Yore et al. report a group of branched fatty acid esters of hydroxy fatty acids that regulate insulin secretion and glucose uptake through the activation of GPR120. Fatty acids are an important class of signaling molecules regulating key aspects of whole body metabolism and physiology. In this issue, Yore et al. report a group of branched fatty acid esters of hydroxy fatty acids that regulate insulin secretion and glucose uptake through the activation of GPR120. Cooking up drugs with the potential to prevent or treat obesity and type 2 diabetes has proven a challenge that might have even been too great for Walter White, the resourceful chemist of the TV’s Breaking Bad. New discoveries focusing on fat cells, however, may offer hope. White adipose tissue, by virtue of its ability to store energy, is central to the regulation of lipid and glucose homeostasis during the fed and fasted state. Recently, fat has also received attention for its ability to increase energy expenditure and counteract the development of obesity and type 2 diabetes. This has been driven mainly by the identification of functional human brown adipose tissue. Nevertheless, dysfunctional white adipose tissue remains one of the primary causes of insulin resistance associated with obesity and the metabolic syndrome. Pharmacological interventions to treat or reverse the consequences of obesity and type 2 diabetes might be more likely to succeed if their target includes white adipose tissue function. In the current issue of Cell, Yore et al., 2014Yore M.M. Syed I. Moraes-Vieira P.M. Zhang T. Herman M.A. Homan E. Patel R.T. Lee J. Chen S. Peroni O.D. et al.Cell. 2014; 159 (this issue): 318-332Abstract Full Text Full Text PDF PubMed Scopus (497) Google Scholar offer such a functional target with the identification of a new class of branched fatty acid esters of hydroxy fatty acids (FAHFA). FAHFA are synthesized in response to Glut4-mediated glucose uptake and activation of the transcription factor ChREBP (Carbohydrate-responsive element-binding protein) in white adipocytes and released in the blood to enhance insulin secretion and increase insulin-stimulated glucose uptake into adipose tissue through the activation of Gpr120 (Figure 1) (Yore et al., 2014Yore M.M. Syed I. Moraes-Vieira P.M. Zhang T. Herman M.A. Homan E. Patel R.T. Lee J. Chen S. Peroni O.D. et al.Cell. 2014; 159 (this issue): 318-332Abstract Full Text Full Text PDF PubMed Scopus (497) Google Scholar). Hence, the authors extend the repertoire of white adipocyte endocrine factors, as well as those from other tissues, to include a previously unrecognized class of fatty acid esters that function as important regulators of glucose homeostasis. Regulation of glucose and lipid homeostasis is a key function of adipocytes, one that critically depends on insulin-mediated glucose uptake by Glut4. In line with this, downregulation of Glut4 in adipose tissue is one of the earliest events in the pathogenesis of insulin resistance and type 2 diabetes. The key role of this pathway is underscored by the ability of adipose tissue selective overexpression of Glut4 (AG4OX mice) to rescue glucose intolerance and insulin resistance in muscle-specific Glut4 knockout mice (Carvalho et al., 2005Carvalho E. Kotani K. Peroni O.D. Kahn B.B. Am. J. Physiol. Endocrinol. Metab. 2005; 289: E551-E561Crossref PubMed Scopus (181) Google Scholar). However, contrary to the general association of increased free fatty acids with insulin resistance, these mice show improved insulin sensitivity and increased serum-free fatty acids. Subsequently, Herman et al., 2012Herman M.A. Peroni O.D. Villoria J. Schön M.R. Abumrad N.A. Blüher M. Klein S. Kahn B.B. Nature. 2012; 484: 333-338Crossref PubMed Scopus (416) Google Scholar established that ChREBP mediates the beneficial effects of enhanced Glut4-mediated glucose uptake in adipocytes by activating de novo lipogenesis. This suggests that in addition to the release of metabolically unfavorable fatty acid metabolites like long chain fatty acid acyl-CoA, diacylglycerol and ceramides, adipocytes could secrete lipid species that are metabolically beneficial, a notion supported by data from the laboratory of Gokhan Hotamisligil, who identified palmitoleate as an adipose-derived lipid hormone improving insulin action in muscle and liver (Cao et al., 2008Cao H. Gerhold K. Mayers J.R. Wiest M.M. Watkins S.M. Hotamisligil G.S. Cell. 2008; 134: 933-944Abstract Full Text Full Text PDF PubMed Scopus (815) Google Scholar). Thus, in addition to the various hormones and cytokines released from adipocytes, lipids, as lipokines, could act as important regulators of whole body metabolism. To test their hypothesis, Yore et al. set out to measure adipose lipids in AG4OX mice using an advanced, untargeted mass spectrometry lipidomics approach, from which they discover a previously unidentified class of fatty acid-hydroxy fatty acids (FAHFAs), consisting of 16 different members. Among this group, palmitic acid-hydroxy stearic acids (PAHSA) are the most highly upregulated fatty acids in adipose tissue of AG4OX mice, which led the authors to investigate the biological regulation and activity of PAHSAs. There are a total of eight different PAHSA isomers in mouse tissues, and each isomer is defined by the position of the ester at a different carbon of the hydroxystearic acid (HSA) in the PAHSA structure. PAHSA levels are reduced with diet-induced obesity and insulin resistance in both mice and humans. These data alone are significant, because they establish PAHSAs as new biomarkers for insulin resistance. Moreover, the correlation between high PAHSA levels and insulin sensitivity prompted the authors to measure the effects of these lipids in vivo. Oral delivery of 9-PAHSA and 5-PAHSA to mice enhances glucose tolerance through their ability to bind to and activate the Gpr120 long-chain fatty acid receptor. In line with this potential function as a natural Gpr120 ligand, PAHSAs enhance insulin secretion through their action on pancreatic islets and Glp-1-secreting intestinal enteroendocrine cells. In addition, similar to the effects of ω-3 fatty acids, PAHSAs reduce lipopolysaccharide- and high-fat-diet-induced inflammation. Further evidence for a connection between PAHSAs and GPR120 is established by demonstrating that insulin-stimulated Glut4 translocation and glucose uptake in adipocytes requires PAHSA-induced GPR120 signaling. Overall, they not only describe the origin and regulation of an entirely new class of signaling metabolites during different metabolic states, like fasting and high fat diet feeding, but also identify Gpr120 as a FAHFA receptor. Yore et al. establish PAHSAs as Gpr120 ligands, defining their physiological functions in increasing insulin secretion and insulin-stimulated glucose transport, thereby modulating glucose homeostasis. However, some of the observed results might not be fully explained by signal mediation through Gpr120. The regulation of Glp-1 secretion, for example, has been associated with both activation of Gpr120 and the functionally closely related Gpr40 (Milligan et al., 2014Milligan G. Alvarez-Curto E. Watterson K.R. Ulven T. Hudson B.D. Br. J. Pharmacol. 2014; (Published online August 18, 2014)https://doi.org/10.1111/bph.12879Crossref PubMed Scopus (57) Google Scholar). Moreover, recently Oh da et al., 2014Oh da Y. Walenta E. Akiyama T.E. Lagakos W.S. Lackey D. Pessentheiner A.R. Sasik R. Hah N. Chi T.J. Cox J.M. et al.Nat. Med. 2014; 20: 942-947Crossref PubMed Scopus (274) Google Scholar described a Gpr120-selective agonist that confers an improvement of glucose tolerance similar to PAHSAs and fails to directly induce Glp-1 secretion. Thus, using Gpr120-deficient animal models it will be interesting to determine if PAHSAs are endogenous Gpr40 ligands too. PAHSAs could also enable the development of powerful coagonists that would simultaneously activate both receptors and, similar to what we have shown for GIP/Glp-1 dual incretin agonists (Finan et al., 2013Finan B. Ma T. Ottaway N. Muller T.D. Habegger K.M. Heppner K.M. Kirchner H. Holland J. Hembree J. Raver C. et al.Sci. Transl. Med. 2013; 5: 209Crossref Scopus (363) Google Scholar), utilize the positive consequences of these receptor activities while reducing the risks of ligand resistance and toxicity. This seems especially important for the activation of Gpr40, as evidenced by the recent failure of a clinical phase III study using Fasiglifam (TAK-875) due to concerns about liver toxicity (Milligan et al., 2014Milligan G. Alvarez-Curto E. Watterson K.R. Ulven T. Hudson B.D. Br. J. Pharmacol. 2014; (Published online August 18, 2014)https://doi.org/10.1111/bph.12879Crossref PubMed Scopus (57) Google Scholar). In addition to their role in Glp-1 secretion, PAHSAs are also directly associated with insulin secretion from pancreatic β-cells. However, recent data suggest that activation of Gpr120 to regulate insulin secretion may be mediated mainly through inhibition of somatostatin release from δ-cells rather than direct action on β-cells, further indicating a potential agonistic action of PAHSAs on Gpr40 (Stone et al., 2014Stone V.M. Dhayal S. Brocklehurst K.J. Lenaghan C. Sörhede Winzell M. Hammar M. Xu X. Smith D.M. Morgan N.G. Diabetologia. 2014; 57: 1182-1191Crossref PubMed Scopus (101) Google Scholar), or other fatty acid receptors. Aside from their pharmacological action, the exact pathways and enzymes responsible for the production and release of FAHFAs remain unknown but are an important piece of the puzzle. The current study demonstrates that enzymes within adipose and liver lysates produce similar amounts of PAHSAs from exogenous substrates, yet tissue levels are dramatically different, indicating that the substrate might be the rate-limiting factor determining tissue abundance. The synthesis of FAHFAs in nonadipose tissues, suggests that FAHFAs, like other signaling lipids, (Gillum et al., 2008Gillum M.P. Zhang D. Zhang X.M. Erion D.M. Jamison R.A. Choi C. Dong J. Shanabrough M. Duenas H.R. Frederick D.W. et al.Cell. 2008; 135: 813-824Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar, Rodríguez de Fonseca et al., 2001Rodríguez de Fonseca F. Navarro M. Gómez R. Escuredo L. Nava F. Fu J. Murillo-Rodríguez E. Giuffrida A. LoVerme J. Gaetani S. et al.Nature. 2001; 414: 209-212Crossref PubMed Scopus (591) Google Scholar), are not specific to adipocytes but can be produced and released from a variety of tissues. Thus, FAHFAs from nonadipose tissues could also contribute to the endocrine effects of these lipids. Yore et al. show that PAHSA levels change dramatically within adipose tissue upon fasting and high-fat-diet feeding. Conversely, overall serum PAHSA levels remain unchanged upon these interventions, indicating that individual PAHSA isomers might show selective, nonredundant functions to mediate changes in Glp-1 and insulin secretion. To date, proteins and peptides remain the focus of endocrinologists who seek to decipher the communication pathways between organs and develop new therapeutic strategies. However, new structurally diverse sets of metabolites, either from within the body or from gut microbiota, have emerged as important regulators of metabolism. The identification of branched fatty-acid-esters of hydroxy-fatty-acids as endocrine factors highlights the significance of metabolomics studies in revealing new targets for the treatment of type 2 diabetes and the metabolic syndrome beyond genomics and proteomics. Identifying other important, and likely existing, bioactive metabolites and using that knowledge to develop personalized therapy options to treat obesity and metabolic syndrome are an opportunity we can’t afford to miss. For now, white adipose tissue has taught us another important (bio-)chemical lesson we suspect even Walter White would have found quite fascinating. The authors thank Julia Schlehe and Silke Morin for language editing. Research in the authors’ labs is (in part) funded by the Helmholtz Alliance ICEMED–Imaging and Curing Environmental Metabolic Diseases, through the Initiative and Networking Fund of the Helmholtz Association, iMed–the Helmholtz Initiative on Pesonalized Medicine and the Else Kröner-Fresenius-Stiftung. Discovery of a Class of Endogenous Mammalian Lipids with Anti-Diabetic and Anti-inflammatory EffectsYore et al.CellOctober 09, 2014In BriefA new class of lipids that are low in insulin-resistant humans promotes glucose tolerance and ameliorates inflammation associated with obesity in mouse models. Full-Text PDF Open Archive" @default.
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